Intermediates useful in preparing propenone oxime ethers

ABSTRACT

The invention relates to new propenone oxime ethers, a method of preparing them and pharmaceutical compositions containing them. Said new propenone oxime ethers have the formula  (* CHEMICAL STRUCTURE *) (I)  in which Ar and Ar&#39; each independently denotes a phenyl group non-substituted, mono or polysubstituted, a 9-anthryl group or a naphthyl group, a pyridyl, thienyl or furyl group; R1 and R2 each independently denotes hydrogen, a C1-C4 alkyl group or together with the N-atom to which they are bonded a 1-pyrrolidinyl, piperidino, morpholino or 1-piperazinyl group; M=H, Cl, Br or a C1-C6 alkyl group n=2 or 3. The invention also deals with the salts of compounds of formula (I). Said compounds have good activity in the anti platelet-clotting tests and are also antagonists of the 5HT2 receptors.

This application is a division of application Ser. No. 07/444,823, filedDec. 1, 1989, now U.S. Pat. No. 5,166,416.

The invention relates to novel 2-propene 1-one φ-substituted oxime ethercompounds comprising various aromatic and heteroaromatic rings inpositions 1 and 3. It also deals with a method of preparing them andpharmaceutical compositions containing them. The compounds according tothe invention have interesting therapeutic properties.

More particularly the compounds have an effect on the central andperipheral nervous system and are antagonists of the 5HT₂ receptors.

Numerous biological processes (appetite, sleep, sexual activity,depression, mood, arterial hypertension) are partly connected with theaction of a neurotransmitter, i.e. serotonin or 5-hydroxy tryptamine or5HT (R. Glennon, Journal of Medicinal Chemistry, 1987, 30, 1).

Their effects are due to interaction of the product with specificbonding sites (5HT receptors) present at the central and peripherallevel (gastro-intestinal tract, lungs, cardiovascular system). Atpresent three types of sites: 5HT₁, 5HT₂ and 5HT₃ --have been described,with sub-types. It appears that type 5HT₂ receptors occur in certaincerebral syndromes and may play a part in clotting of platelets (F. DECLERK et al., Biochemical Pharmacology, 1984, 33, 2807), arterialhypertension and migraines (G. JOHNSON, Reports in Medicinal Chemistry,1987, 4150) and the contraction of smooth muscles (L. COHEN et al.,Journal of Pharmacology and Experimental Therapeutics, 1981, 218, 421).

Diphenyl alkanol ether and diphenyl alkanone oxime ether derivativeshaving antispasmodic and anti blood-clotting activity and effects oncerebral insufficiency and senile dementia are described in Europeanpatent 0 017 217.

More particularly the compound ##STR2## is described among productshaving cerebral vasodilating properties.

It has now been found that certain propenone oxime ethers are compoundshaving a high affinity for the 5HT₂ receptor.

It has also been found that the aforementioned propenone oxime ethershave interesting pharmacological properties, inter alia a good antiblood-clotting effect, and are useful inter alia for treatment of anydisease depending on 5HT.

According to one of its features, therefore, the invention relates topropenone oxime ethers having the formula: ##STR3## in which Ar and Ar'can each independently denote either:

(a) a phenyl group, non-substituted or mono or polysubstituted by ahalogen atom, a lower alkyl grouping (containing 1 to 4 carbon atoms), anitro, hydroxyl, alkoxy (1-4 carbon atoms), acyloxy (1-4 carbon atoms),dimethylamino or carboxyalkoxy grouping in which the alkylene contains1-4 carbon atoms; or a 9-anthryl group or a naphthyl group, or

(b) a heteroaromatic group chosen from among pyridyl, thienyl or furylgroups;

R₁ and R₂ each independently denote a hydrogen atom or a lower alkylgrouping (1-4 carbon atoms) or R₁ and R₂ together with the nitrogen atomto which they are bonded constitute a 1-pyrrolidinyl or piperidino ormorpholino or 1-piperazinyl grouping;

M represents a hydrogen atom or a chlorine or bromine atom, or astraight or branched lower alkyl containing 1-6 carbon atoms, and

n=2 or 3,

and their salts with mineral or organic acids.

Among the heteroaromatic groups, 3-pyridyl, 2-thienyl, 3-thienyl or2-furyl are preferred groups.

The mineral or organic acids which form the addition salts according tothe invention comprise acids of use for suitable separation orcrystallization of formula I compounds, e.g. picric acid or oxalic acid,or acids for forming pharmaceutically acceptable salts such as thehydrochloride, hydrobromide, sulphate, hydrogen sulphate, dihydrogenphosphate, methane sulphonate, methyl sulphate, maleate, fumarate,naphthalene sulphonate or isethionate.

As is known, compounds having the formula ##STR4## where Ar and Ar' havethe previously-given meanings, such compounds being called "chalcones",occur preferentially in the trans form with respect to the propenedouble bond (Bull. Soc. Chim. France, 1961, 5, 1369).

The compounds (I) according to the invention are oximes of chalcones andhave a trans geometry with respect to the carbon-carbon double bond.

With regard to the geometry of the C═N bond of the φ-substituted oxime,the formula ##STR5## indicates that the substance is a mixture invarious proportions of the syn(s) and anti(a) isomers, which arerepresented as follows (J. Chem. Soc., 1981, 860): ##STR6##

In a preferred embodiment, the invention relates more particularly to apropenone oxime ether according to (I), having the formula: ##STR7##where Ar'_(a) represents an aromatic group chosen from among pyridyl,thienyl, furyl or 9-anthryl and W₁ and W₂ each independently represent ahydrogen atom or a halogen atom or a lower alkyl grouping (1-4 carbonatoms) or a nitro or hydroxyl or alkoxy (1-4 carbon atoms) or acyloxy(1-4 carbon atoms) or dimethylamino or carboxyalkoxy group in which thealkylene contains 1 to 4 carbon atoms, or a salt thereof with mineral ororganic acids.

According to another embodiment, the invention relates more particularlyto a propenone oxime ether according to (I), having the formula:##STR8## in which Ar_(a) represents a group chosen from among pyridyl,thienyl, furyl or 9-anthryl and W'₁ and W'₂ each independently representa hydrogen atom or a halogen atom or a lower alkyl grouping (1 to 4carbon atoms) or a nitro, hydroxyl, alkoxy (1 to 4 carbon atoms) acyloxy(1 to 4 carbon atoms), dimethylamino or carboxyalkoxy group in which thealkylene contains 1 to 4 carbon atoms, or a salt thereof with mineral ororganic acids.

Other preferred compounds according to the invention have the formula:##STR9## in which W₁, W₂, W'₁, W'₂ can independently denote a hyrogenatom or a halogen atom or a lower alkyl grouping (1-4 carbon atoms) or anitro or hydroxyl or alkoxyl (1-4 carbon atoms) or acyloxy (1-4 carbonatoms) or dimethylamino or carboxyalkoxy group in which the alkylenecontains 1 to 4 carbon atoms; ##STR10## in which the substituents are a2-thienyl or a 3-thienyl.

The compounds are in base or salt form with mineral or organic acids.

According to another feature, the invention relates to a method ofpreparing formula (I) compounds and salts thereof, characterised in that

a) a chalcone having the formula: ##STR11## is treated with ahydroxylamine having the formula:

    H.sub.2 NOZ                                                (III)

in which Z represents either

an aminoalkyl chain having the formula: ##STR12## where R₁ and R₂ havethe meanings described for (I), or a hydrogen atom or

a substituted alkyl group having the formula:

    --(CH.sub.2).sub.n X

where X represents a starting group; and in that

b) the resulting product having the formula: ##STR13## where Ar and Ar'are as defined hereinbefore and where Z represents hydrogen or the--(CH₂)_(n) X group is then, when Z is hydrogen and in the presence of abasic condensation agent, treated either with an amine having theformula: ##STR14## in which R₁ and R₂ are as defined hereinbefore and X'is a starting group or, when Z represents a group

    --(CH.sub.2).sub.n --X

where X is as defined hereinbefore, the resulting product is treatedwith an amine having the formula: ##STR15## where R₁ and R₂ are asdefined hereinbefore, and in that

c) the product thus obtained in (a) or (b) is converted if necessaryinto one of its salts.

The starting groups represented by X and X' can be one of thesubstituents generally used for preparing alkylamines, e.g. a halogenatom or a hydroxysilyl or hydroxy group esterified with methanesulphonicacid.

The following reaction diagram indicates the method of preparing thecompounds according to the invention: ##STR16##

The choice of the method of synthesis will depend on the availability ofthe various hydroxylamines and the method of preparation thereof.

Salts of hydroxylamines 100-substituted by an alkylamino chain havingthe formula: ##STR17## can be prepared by methods described in theliterature (Chimia, 1964, part 1, 18, 1, 36) and can yield the compoundsI according to the invention in a single reaction with chalcones (II) ina solvent such as reflux-heated ethanol.

The hydroxylamine salt condensed on to a chalcone (II) in alcohol orpyridine yields the oxime having the formula: ##STR18## which is thentreated in a first step with a base such as sodium hydride or potassiumcarbonate in a polar aprotic solvent such as dimethyl formamide,dimethyl acetamide or dimethyl sulphoxide, and is then substituted by analkylamine (V) comprising a starting grouping X' having the formula:##STR19## yielding the compounds (I) according to the invention.

In another variant of the general method of synthesis, a chalcone (II)is reacted in an alkanol at ambient temperature with an φ-alkylatedhydroxylamine salt, for example hydrochloride having the formula:

    HC1, H.sub.2 N--O(CH.sub.2).sub.n X                        (IIIc)

comprising a starting grouping X, so as to obtain the intermediatehaving the formula: ##STR20## which is then substituted by an amine,either in a solvent such as water or dimethyl formamide or in theabsence of a solvent and in the presence only of the amine, thus finallyyielding the compounds (I) according to the invention.

After thus being obtained, the formula (I) product is isolated in theform of the free base or salt, by conventional methods.

When the formula (I) compound is obtained in the form of the free base,it is converted into a salt by treatment with the chosen acid in anorganic solvent. The free base, dissolved e.g. in an alcohol such asisopropanol, is treated with a solution of the chosen acid in the samesolvent, thus obtaining the corresponding salt, which is isolated byconventional techniques. This method is used e.g. for preparing thehydrochloride, hydrobromide, sulphate, hydrogen sulphate, dihydrogenphosphate, methane sulphonate, methyl sulphate, oxylate, maleate,fumarate, 2-naphthalene sulphonate and isethionate.

At the end of the reaction between compound (II) and compound (III), theformula (I) compound can be isolated in the form of one of its salts,e.g. the hydrochloride or the oxalate. In that case, if necessary, thefree base can be prepared by neutralizing the salt with a mineral ororganic base such as sodium hydroxide or triethylamine or analkali-metal carbonate or bicarbonate such as sodium or potassiumcarbonate or bicarbonate, and can then if required be converted intoanother of its salts.

The configuration of an isomer and the relative proportions of a mixtureof syn and anti isomers are determined by NMR.

The syn and anti isomers in a mixture are separated by crystallizationof salts such as oxalates, maleates, fumarates and hydrochlorides ofcompounds having the formula (I).

The chalcones (II) are known or prepared by methods described in theliterature (Houben Weyl 10-1, 1181) by Claisen-Schmidt condensation, byreacting an aldehyde Ar--CHO with a ketone Ar'--CO--Alk (Alk representsan alkyl containing 1 to 7 carbon atoms).

Carrying out the process of the invention, novel derivatives of2-propene 1-one of formula (II) may be used. Such novel derivatives--key intermediates--constitute another subject of the invention, moreparticulary those of formula: ##STR21##

Such derivatives are prepared by known methods. For example, the onebearing a thiophenic derivative may be prepared by substitution of a3-thiophene carboxaldehyde with a 3-acetyl thiophene.

The compounds according to the invention have been subjected tobiological and pharmacological tests and compared with the prior-artcompound (A).

The compounds (I) have good activity in the anti platelet-clotting testafter T. HALLAM et al. Thrombosis Research 1982, 27, 435-445. The 50inhibiting concentration of the most active compounds is 5 to 50 timesas small as that of compound (A).

Also, compounds (I) have high affinity in vitro and in vivo for 5HT₂receptors.

These tests are carried out under the experimental conditions describedby J. LEYSEN et al., Molecular Pharmacology, 1982, 21, 301-314 asregards the tests in vitro and as per J. FROST et al., Life Sciences,1987, 40, 987-997 as regards the tests in vivo.

Stimulation of a rabbit's abdominal aorta strip shows activity 50 to1500 times as great as that of product (A), with regard to antagonism toperipheral 5HT receptors. The tests were made after E. APPERLEY et al.,Br. J. of Pharmacol., 1976, 58, 211-221.

The compounds according to the invention are also antagonists of thecentral 5HT₂ receptors. This activity was shown by the head-twitch testmade after C. GOURET, J. Pharmacol., Paris, 1975, 6, 165-175.

The compounds also have an anti-convulsing activity shown by the test onantagonism to clonic spasms induced by pentetrazole (antagonism to thecentral 5HT₂ receptors) after P. WORMS et al., J. Pharmacol. Exp. Ther.,1982, 220, 660-670.

The formula (I) compounds have low toxicity. More particularly theiracute toxicity is compatible with use thereof as drugs, e.g. to preventclotting of platelets, or as psychotropic drugs.

For this purpose, mammals requiring this treatment are given aneffective quantity of the formula (I) compound or of one of itspharmaceutically acceptable salts.

The aforementioned formula (I) compounds and their pharmaticeuticallyacceptable salts can be used in daily doses of 0.01 to 10 mg perkilogram body weight of the mammal under treatment, preferably at dailydoses of 0.1 to 5 mg/kg. In man, the dose can preferably vary from 0.5to 500 mg per day, more particularly from 2.5 to 250 mg depending on thepatient's age or the type of treatment, i.e. whether prophylactic orcurative.

The formula (I) compounds are generally administered in unit doses. Theunit doses are preferably formulated in pharmaceutical compositions inwhich the active principle is mixed with a pharmaceutical excipient.

According to another feature, therefore, the invention relates topharmaceutical compositions in which the active principle is anaforementioned formula (I) compound or a pharmaceutically acceptablesalt thereof.

In the pharmaceutical compositions according to the invention for oral,sublingual, subcutaneous, intramuscular, intravenous, transdermic, localor rectal administration, the aforementioned formula (I) activeingredients can be administered in unit forms of administration, mixedwith conventional pharmaceutical excipients, to animals and to man. Thesuitable unit forms of administration comprise oral forms such astablets, capsules, powders, granules and oral solutions or suspensions,sublingual and buccal forms of administration, subcutaneous,intramuscular, intravenous, intranasal or intraocular forms ofadministration and rectal forms of administration.

Each unit dose can contain 0.1 to 500 mg of active ingredient,preferably 2.5 to 125 mg, in combination with a pharmaceuticalexcipient. Each unit dose can be administered 1 to 4 times per day.

When a solid composition is prepared in tablet form, the main activeingredient is mixed with a pharmaceutical excipient such as gelatine,starch, lactose, magnesium stearate, talc, gum arabic or the like. Thetablets can be coated with saccharose or suitable other substances ortreated so that they have prolonged or delayed activity and so that theycontinously release a given quantity of the active principle.

A preparation in capsules is obtained by mixing the active ingredientwith a diluent and pouring the resulting mixture into soft or hardcapsules.

A preparation in syrup or elixir form can contain the active ingredienttogether with a sweetener, preferably without calories, and methylparaben and propyl paraben antiseptics and a suitable flavouring anddye.

The powders or granules dispersible in water can contain the activeingredient mixed with dispersing agents or wetting agents or suspensionagents such as polyvinyl pyrrolidone, and with sweeteners or tasteadjusters.

Rectal administration is made via suppositories prepared with binderssuch as cocoa butter or polyethylene glycols, which melt at the rectaltemperature.

Parenteral, intranasal or intraocular administration is via aqueoussuspensions, or isotonic saline solutions or sterile injectablesolutions containing pharmacologically compatible dispersing and/orwetting agents, e.g. propylene glycol or butylene glycol.

Alternatively the active principle can be formulated in microcapsules,with one or more excipients or additives if required.

The following examples illustrate the invention without limiting it.

The NMR spectra were recorded at 250 MHz. The positions of the signalswere given in millionths with respect to trimethyl silyl propanesulphonate, and the spectra were obtained in deuterated dimethylsulphoxide.

The coupling constants J are given in Hertz (Hz).

The following abbreviations are used:

s: singlet

d: doublet

t: triplet

m: multiplet

se: widened signal

The symbol "*" in the Tables indicate that the main chemicaldisplacements (position of singlets or of the middle of doublets,triplets or multiplets) of the compound in question are described inTable 6.

The relative proportions of syn and anti isomers (%a - %s) weredetermined by NMR.

The instantaneous melting-points (MP) of the recrystallized productswere measured on a Kofler heating bench and are expressed in degreesCelsius.

EXAMPLE 1 Trans 1-N,N-dimethyl aminoethoxyimino 1-phenyl3-(4-hydroxyphenyl) 2-propene; CM 40414=mixture of 20% syn isomer and80% anti isomer. ##STR22## a) 4-hydroxy chalcone

Prepared as per Chemistry of Carbon Compounds, E. H. Rodd, 1956, vol.III⁸, 1186

b) 2-N,N-dimethylamino ethoxyamine hydrochloride

Prepared as per Bull. Soc. Chim. France, 1958, 5, 664.

c) CM 40414

15 g of 4-hydroxy chalcone a) and 15 g of the compound prepared as perb) were heated with reflux and under agitation in 150 ml of absoluteethanol for 5 hours.

Concentrate the ethanol in vacuo, dissolve the residue in 200 ml of 10%acetic acid in water, wash with methylene chloride, alkanise the aqueousphase with sodium bicarbonate, extract with methylene chloride, decantthe chloromethylene phase, wash it with water, decant, dry overmagnesium sulphate, filter and concentrate in vacuo. Recrystallise theresidue from 500 ml ethyl acetate.

M=13 g

M.P.=175° C.

The isomer mixture contained 20% syn isomer and 80% anti isomer.

NMR spectrum: ##STR23##

2.05 and 2.15 (6H: 1.2H syn and 4.8H anti, s, N(CH₃)₂); 2.4 and 2.55(2H: 0.4H syn and 1.6H anti, t, J=6, CH₂ N); 4.05 and 4.2 (2H: 0.4H synand 1.6H anti, t, J=6, OCH₂); 6.2 and 6.6 (1H: 0.2H syn and 0.8H anti,d, J_(trans) =16, H--C═); 6.85 and 7.25 (1H: 0.2H syn and 0.8H anti, d,J_(trans) =16, H--C); 6.72 (2H, d, J_(ortho) =8, H₃,5); 7.30 (2H, d, J:8, H₂,6); 7.40 (5H, s, H_(2'),3',4',5',6').

Separation of syn and anti isomers d) Trans1-N,N-dimethylaminoethoxyimino 1-phenyl 3-(4-hydroxyphenyl) 2-propanehemifumarate; anti isomer, SR 45007 A

12.3 g of CM 40414 obtained previously were dissolved when hot in 220 mlof isopropanol and 4.6 g fumaric acid were added. Allow the solution toreturn to ambient temperature then leave with agitation for 11/2 hours.Filter the fumarate and rinse it with ether.

M=11.6 g

M.P.=186°-187° C.

RMN spectrum:

2.4 (6H, s, N(CH₃)₂); 2.85 (2H, t, J=6, N--CH₂); 4.25 (2H, t, J=6,OCH₂); 6.48 (1H, s, fumarate); 6.6 (1H, d, J_(trans) =16, H--C═); 6.7(2H, d, J_(ortho) =8, H₃,5) 7.3 (1H, d, J_(trans) =16, H--C═); 7.35 (2H,d, J_(ortho) =8, H₂,6); 7.45 (5H, s, H_(2'),3',4',5',6').

e) Trans 1-N,N-dimethylaminoethoxyimino 1-phenyl 3-(4-hydroxyphenyl)2-propene hemifumarate, syn SR 45008 A isomer

Concentrate the previously-obtained filtered fumarate in vacuo, dissolveresidue in 50 ml acetone, separate insoluble substance by filtrationthen add ether until turbid and leave to crystallize. Filter theprecipitate and recrystallize it from isopropanol.

M=2.0 g

M.P.=157°-159° C.

NMR spectrum:

2.2 (6H, s, N(CH₃)₂); 2.7 (2H, t, J=6, NCH₂); 4.15 (2H, t, J=6, OCH₂);6.2 (1H, D, J_(trans) =16, H--C═); 6.45 (1H, s, fumarate); 6.7 (2H, d,J_(ortho) =8, H₃,5); 6.9 (1H, d, J_(trans) =16, H--C═); 7.25 (2H, d,J_(ortho) =8, H₂,6); from 7.15 to 7.50 (5H, solid, H_(2'),3',4', 5',6').

Isomerization starting from the anti isomer, SR 45007 A.

In order to prepare the syn isomer, obtained in a smaller proportionduring synthesis, the anti isomer was treated as follows afterisolation:

17.7 g of SR 45007 A were dissolved in 200 ml absolute ethanol and 9.5ml concentrated hydrochloric acid. Reflux-heat the reaction mixture for6 hours then leave at ambient temperature overnight. Concentrate invacuo, dissolve residue in water, make alkaline with sodium bicarbonate,filter the precipitate, rinse with water and dry.

m=15.1 g of a mixture of 25% syn isomer and 75% anti isomer.

The mixture was converted into a salt as per d) hereinbefore by fumaricacid to give the anti isomer, and the filtered fumarate was treated asper e) hereinbefore to obtain the syn isomer.

EXAMPLE 2 Trans 1-N,N-dimethyl aminoethoxyimino 1-phenyl3-(4-methoxyphenyl) 2-propene oxalate: SR 45999 ##STR24##

A mixture of 10 g 4-methoxy chalcone and 8.9 g of 2-N,N-dimethylaminoethoxyamine dihydrochloride in 150 ml absolute ethanol was reflux-heatedfor 7 hours.

Leave the reaction mixture to cool, filter the excess reagent andconcentrate the filtrate in vacuo. Dissolve residue in water wash withether, make the aqueous phase alkaline with a solution of concentratedammonia, extract with ether, wash with water, dry over magnesiumsulphate and concentrate in vacuo.

The yield was 12 g of an oil which was chromatographed on silica gel inorder to separate the syn and anti isomers.

Eluent: methylene chloride/ethanol 97/3 (v/v)

The less polar product was eluted, yielding 6.5 g of an oil to which 1.7g oxalic acid in 150 ml acetone were added to obtain 6.64 g of antiisomer: SR 45999 A

M.P.=162° C.

The more polar product was eluted, yielding 1.6 g of an oil to which0.45 g oxalic acid in 20 ml acetone was added, giving 1.38 g of the synisomer: SR 45996 A.

M.P.=179° C.

EXAMPLE 3 Trans 1-N,N-dimethylaminoethoxyimino 1-(4-methoxyphenyl)3-(4-hydroxyphenyl) 2-propene hydrochloride ##STR25## a) Anti isomer: SR45175 A

A mixture of 3 g of 4-hydroxy 4'-methoxy chalcone and 3.1 g of2-N,N-dimethylaminoethoxyamine dihydrochloride in 50 ml ethanol wasreflux-heated for 6 hours.

Leave the reaction mixture to cool, filter the crystals, agitate in 20ml water, filter and dry to obtain 2.6 g of the anti isomer.

M.P.=216° C.

b) Mixture of 25% syn isomer and 75% anti isomer; SR 45286

Concentrate the previously-obtained ethanolic filtrate in vacuo,dissolve residue in 100 ml water, extract twice with ethyl acetate, makealkaline at pH 8 with sodium bicarbonate, decant the aqueous phase andextract it three times with methylene chloride, wash in water, decant,dry a magnesium sulphate, and concentrate in vacuo to obtain 0.58 g of agum which crystallises. Dissolve the crystals in 3 ml of a 70-30 (v/v)mixture of toluene and petroleum ether and filter to obtain 250 mg of amixture of 25% syn isomer and 75% anti isomer.

M.P.=148° C.

EXAMPLE 4 Trans 1-N,N-dimethylaminoethoxyimino 1-phenyl3-(4-acetoxyphenyl) 2-propene hemifumarate. Syn isomer: SR 46024 A##STR26##

1.2 g of the previously-described SR 45008 A were agitated at ambienttemperature overnight in 12 ml acetic anhydride.

Concentrate the excess acetic anhydride in vacuo at 20°-30° C., add 30ml methylene chloride, wash in water, decant the chloromethylene phase,dry over magnesium sulphate, concentrate the methylene chloride invacuo, dissolve residue in ethyl ether, filter the precipitate andrecrystallize it from ethanol, adding ether until turbid, m=0.7 g.

EXAMPLE 5 Trans 1-N,N-dimethylaminoethoxyimino di-1,3-(3-thienyl)2-propene acid oxalate: SR 45557 A ##STR27## a) Preparation of transdi-1,3(3-thienyl) 2-propene 1-one

2.25 g of 3-thiophene carboxaldehyde and 2.52 g of 3-acetyl thiophenewere dissolved in 10 ml absolute ethanol.

A solution of 0.4 g NaOH in 1 ml water was added dropwise to thesolution, cooled in ice.

The reaction mixture was agitated at 0°-5° C. for 3 hours. Theprecipitate was filtered, rinsed in water, dissolved in ether and driedover magnesium sulphate. The ether was concentrated in vacuo and theresidue was recrystallized from cyclohexane.

M=2.8 g

M.P.=81° C.

NMR spectrum.

7.58 et 7.83 (6H, m, H_(thiophene), --C H═CH--); 8.08 (1H, d, H₄), 8.77(1H, d, H₄).

b) SR 45557 A

The thiophene derivative obtained as per a) was condensed with2-N,N-dimethylaminoethoxyamine dihydrochloride as per Example 12c)hereinbefore, yielding trans 1-N,N-dimethylaminoethoxyimino 1,3di(3-dithienyl) 2-propene, which was converted into a salt with oxalicacid, giving the acid oxalate in a mixture of 75% anti isomer and 25%syn isomer.

M.P.=138° C.

EXAMPLE 6 Trans 1-N,N-dimethylaminoethoxyimino 1-(3-thienyl)3-(4-hydroxyphenyl) 2-propene: SR 45047. ##STR28## a) Preparation oftrans 1-(3-thienyl) 3-(4-hydroxyphenyl) 2-propene 1-one

10 g 4-hydroxybenzaldehyde and 10.4 g 3-acetyl thiophene were dissolvedin 40 ml of a solution of 4% hydrochloric acid in acetic acid.

Agitate the reaction mixture at ambient temperature for 4 days.

Filter the precipitate, rinse with a mixture of 50% acetic acid/waterthen recrystallize from 30 ml ethanol. Filter the crystals.

M=8.1 g

M.P.=158° C.

NMR spectrum:

6.79 (2H, d, J_(ortho) =8, H₃,5); 7.6 (4H, m, 2H:HC--C═et2H_(thiophene)); 7.67 (2H, d, J_(ortho) =8, H₂,6); 8.69 (1H, m,H_(thiophene)); 10.05 (1H, se, OH).

b) SR 54047

The thiophene derivative obtained as per a) was condensed with2-N,N-dimethylaminoethoxyamine hydrochloride as per Example 1c)previously described, yielding SR 45047, a mixture of 75% anti isomerand 25% syn isomer.

M.P.=170° C.

EXAMPLE 7 Trans 1-N,N-dimethylaminoethoxyimino 1-(2-thienyl)3-(4-hydroxyphenyl) 2-propene: SR 45051 ##STR29## a) Preparation oftrans 1-(2-thienyl) 3-(4-hydroxyphenyl) 2-propene 1-one

12.75 g of 2-acetyl thiophene and 12.10 g of 4-hydroxy benzaldehyde weredissolved in 20 ml water. Add a solution of 12.5 g NaOH in 12.5 ml waterand agitate the reaction mixture at ambient temperature for 4 days.

Pour the reaction mixture into 300 ml of 10% hydrochloric acid, filterthe precipitate, dissolve in 200 ml methanol, add vegetable carbon,filter over celite, concentrate the filtrate in vacuo, dissolve theresidue in water, make alkaline at pH 11 and extract with ether.

Add hydrochloric acid until a precipitate forms, and filter.Chromatograph over silica gel, using hexane and ethyl acetate (70-30v/v) as eluent. The fraction containing the expected product isconcentrated in vacuo and the residue is recrystallized from methylenechloride.

M=2.43 g.

NMR spectrum

6.79 (2H, d, J_(ortho) =8, H₃,5); 7.61 (2H, s, HC═CH); 7.68 (2H, d,J_(ortho) =8, H₂,6); 7.24; 7.96; 8.22 (3H, m, H_(thiophene)).

b) SR 45051

The thiophene derivative obtained as per a) was condensed with2-N,N-diethylaminoethoxyamine as per Example 1c) described hereinbefore,yielding SR 45051, a mixture of 20% anti isomer and 80% syn isomer.

M.P.=140° C.

EXAMPLE 8 Trans 1-N,N-dimethylaminoethoxyimino 1-phenyl 3-(3-methoxy4-hydroxyphenyl) 2-propene: SR 45744 ##STR30##

This compound was prepared as per Example 1. A mixture of 76% antiisomer and 24% syn isomer was obtained after recrystallization fromethanol.

M.P.=152° C.

EXAMPLE 9 Trans 1-N,N-dimethylaminoethoxyimino 1-(2-chlorophenyl)3-(4-hydroxyphenyl) 2-propene syn.: SR 46220 ##STR31## A) Preparation ofthe chalcone from 4-hydroxy benzaldehyde 2'-chloro 4-hydroxy chalcone

20 g of 2-chloro acetophenone and 15.8 g 4-hydroxy benzaldehyde weredissolved in 100 ml ethanol saturated with gaseous hydrochloric acid andthe mixture was left at ambient temperature for 3 days. The ethanol wasconcentrated in vacuo. The residue was dissolved in 200 ml isopropanol,after which 500 ml water was added with agitation and the precipitatewas filtered. The yield after recrystallization from isopropanol was25.4 g of the expected chalcone.

M.P.=141° C.

B) Preparation of the chalcone from 4-methoxy benzaldehyde a) 2'-chloro4-methoxy chalcone

30 g of 2-chloro acetophenone and 26.4 g 4-methoxy benzaldehyde wereintroduced into a mixture, cooled in ice, of 1.8 g soda pellets, 88 mlwater and 55 ml 0.950 alcohol. The temperature was kept between 20° and25° C. and the reaction mixture was agitated for 4 hours, then left at5° C. for 10 hours. 150 ml of ice water were the added to the mixtureand a precipitate was separated by filtration and then washed in waterand in ethanol to obtain the expected chalcone.

m=50.6 g

M.P.=83° C.

b) 2'-chloro 4-hydroxy chalcone

30 g of chalcone obtained previously was dissolved in 150 mldichloromethane. The solution was cooled to -70° C. after which 28.4 mlof boron tribromide were added. After the addition, the reaction mixturewas agitated at ambient temperature for 2 hours, then poured on to 200 gof ice. The precipitate was filtered then recrystallized from ethanol.

m=17 g

M.P.=141° C.

SR 46220

4 g of 2'-chloro 4-hydroxy chalcone obtained previously and 4 g of2-N,N-dimethylaminoethoxyamine dihydrochloride were dissolved in 100 mlethanol and the reaction mixture was agitated at 40° C. for 72 hours.

The ethanol was concentrated in vacuo and the residue was dissolved inwater and washed with ethanol. The aqueous phase was made alkaline witha solution of sodium bicarbonate and extracted with methylene chloride.After drying and filtration, the organic phase was concentrated in vacuoand the residue was dissolved in ether, yielding 3.25 g of SR 46620containing 50% a and 50% s.

EXAMPLE 10 Preparation of the oxalate of SR 46220: SR 46220 A

0.53 g of SR 46620 and 0.138 g of oxalic acid were dissolved in 5 mlacetone. The mixture was agitated at ambient temperature for 1 hour thenfiltered, yielding 0.45 g of oxalate which was recrystallized fromethanol/ether, yielding 0.17 g of SR 46220 A (97% syn - 3% anti).

M.P.=205° C.

EXAMPLE 11 Trans 1-N,N-dimethylaminoethoxyimino 1-(2-fluorophenyl)3-(4-hydroxyphenyl) 2-propene syn: SR 46349 ##STR32## A) Preparation ofthe chalcone from 4-methoxy benzaldehyde a) 2'-fluoro 4-methoxy chalcone

100 g of 2-fluoro acetophenone and 98.55 g of 4-methoxy benzaldehydewere dissolved in 360 ml of 2N ethanol hydrochloride then left at 5° C.for 6 days. 500 ml water was then added to the reaction mixture and theprecipitate was filtered, giving 120 g of the expected chalcone.

M.P.=55° C.

b) 2'-fluoro 4-hydroxy chalcone (SR 47035)

The procedure was as per Example 9 hereinbefore. the demethylatedchalcone was obtained by action of boron tribromide.

M.P.=133° C. (isopropanol)

B) Preparation of the chalcone from 4-hydroxy benzaldehyde. SR 47035

100 g of 2-fluoro acetophenone and 88.4 g of 4-hydroxy benzaldehyde weredissolved in 2N ethanol hydrochloride, then left at 5° C. for 9 days.1.2 litres of water was then added with agitation and the precipitastewas filtered, washed by trituration in water and filtered. Theprecipitate was dried then recrystallized from 2.5 litres of toluene,yielding 140.6 g of the expected chalcone.

M.P.=128° C.

C) SR 46349

85 g of the previously obtained chalcone and 85 g of2-N,N-dimethylaminoethoxyamine dihydrochloride were dissolved in 1.5 lof 2N ethanol hydrochloride and reflux-heated for 5 hours. The mixturewas concentrated in vacuo and the residue was dissolved in water, madealkaline with ammonia and fractionated as follows:

pH 5.8-6: 10.5 g anti (SR 46615 example No. 29)

pH 6-6.5: 84.9 g 45% a-55% s

pH>7.5: 7 g syn. M.P.=162° C.: SR 46349

If made alkaline directly at pH>8, the base is obtained, comprising 44%syn and 55% anti.

NMR spectrum of SR 46349

2.00 (6H, s, N (CH₃)₂); 2.40 (2H, t, O CH₂ CH₂ N--); 4.05 (2H, t, O CH₂CH₂ N--); 6.15 (1H, d, H--C═); 6.65 (2H, d, H₃,5) 6.90 (1H, d, H--C═);7.1 a 7,5(6H, m, H_(3'),4',5',6' et H₂,6); 9.70 (1H, s, ArOH)

Oximation of chalcone SR 47035 can alternatively be brought about using2-N,N-dimethylaminoethoxyamine hydrochloride in ethanol in the presenceof methanesulphonic acid or hydrochloric acid, to obtain the expectedoxime.

EXAMPLE 12 Trans 1-N,N-dimethylaminoethoxyimino 1-(2-fluorophenyl)3-(4-hydroxyphenyl) 2-propene hemifumarate syn. SR 46349 B. A)Separation of the syn and anti isomers starting from SR 46349 (45% syn,55% anti) by forming the hemifurmarate

A homogeneous mixture of 41.2 g of crystallized SR 46439 and 7.23 g offumaric acid was prepared. 300 ml of 95° ethanol was then added withagitation at ambient temperature for 11/2 hours. The mixture was thenfiltered, yielding 18 g of syn hemifumarate which was recrystallizedfrom 95° ethanol at 60° C.

m=9 g

M.P.=190° C.

NMR spectrum:

2.20 (6H, s, N (CH₃)₂);

2.68 (2H, t, O--CH₂ CH₂ N--);

4.20 (2H, t, O--CH₂ CH₂ N--);

6.25 (1H, d, H--C=);

6.53 (1H, s, fumarate);

6.75 (2H, d, H₃.5);

6.95 (1H, d, H--C=);

7.2 a 7.6 (6H, m, H_(3'),4',5',6' et H₂,6);

9.6 to 12 (widened signal, --CO₂ H +DOH;

9.90 (1H, s, Ar--OH)

B) Isomerization of SR 46615 A (anti isomer of the hemifumarate of SR46349)

45 g of anti hemifumarate of SR 46349 was dissolved in 500 ml 95°ethanol in the presence of 80 ml concentrated hydrochloric acid. Themixture was then reflux-heated for 6 hours, with exclusion of light,then concentrated in vacuo. The residue was dissolved in water andwashed with ether. The aqueous phase was then made alkaline with ammoniaand a precipitate was separated by filtration.

The yield was 35.7 g of base (45% syn+55% anti), which was treated asbefore, yielding SR 46349 B.

EXAMPLE 13 Trans 1-N,N-dimethylaminoethoxyimino 1-(2-methoxyphenyl)3-(4-hydroxyphenyl) 2-propene oxalate, syn: SR 46023 A ##STR33##

2.6 g of oxalic acid was added to a suspension of 10 g of1-N,N-dimethylaminoethoxyimino 1-(2-methoxyphenyl) 3-(4-hydroxyphenyl)2-propene (SR 45743, 54% anti+46% syn) in 200 ml acetone, and agitatedfor an hour. The oxalate was then filtered and agitated in 10 ml ethanoland then filtered, yielding 1.9 g of syn oxalate.

M.P.=192° C.

NMR spectrum:

2.60 (6H, s, N (CH₃)₂);

3.25 (2H, t, O--CH₂ CH₂ N--);

3.70 (3H, s, Ar'--O CH₃);

4.30 (2H, t, O--CH₂ CH₂ N--);

6.20 (1H, d, H--C═);

6.70 (2H, d, H₃,5);

6.90 (1H, d, H--C═);

6.95 a 7,5 (6H, m, H_(3'),4',5',6' and H₂,6);

9.80 (1H, s, Ar--OH);

7 a 9,5 (se, H oxalate+DOH)

The products according to the invention, synthesized under experimentalconditions similar to those in Examples 1 to 13, are listed in Tables 1,2 and 3 hereinafter.

The following abbreviations have been used in the Tables to denote therecrystallization solvents:

EtOH: ethanol

iPrOH: isopropyl alcohol

DMF: dimethylformamide

AcOEt: ethyl acetate

CH₃ CN: acetonitrile

Tert-BuOH: tertiobutanol

BuOH: butanol

                                      TABLE 1                                     __________________________________________________________________________    Examples 14 to 55                                                              ##STR34##                                   (I)                               n°Examplen° SRProduct                                                W.sub.1 '                                                                          W.sub.1                                                                              n                                                                               ##STR35##                                                                             baseorSalt                                                                            % a-% sIsomer                                                                      recryst.SolventF,                    __________________________________________________________________________                                            °C.                            40258 A                                                                            H    H      2 N(CH.sub.3).sub.2                                                                     oxalate a    170                                   14                         acid         acetone                               45048 A                                                                            H    H      2 N(CH.sub.3).sub.2                                                                     hemi    s    180                                   15                         oxalate      acetone                               45560 A                                                                            H    H      3 N(CH.sub.3).sub.2                                                                     oxalate 65a- 35s                                                                           160                                   16                         acid         EtOH                                  45071                                                                              H    2-OH   2 N(CH.sub.3).sub.2                                                                     base    a    159                                   17                                      AcOEt                                 40613                                                                              H    3-OH   2 N(CH.sub.3).sub.2                                                                     fumarate                                                                              a    140-2                                 18                                      EtOH                                  45172                                                                              H    4-OH   3 N(CH.sub.3).sub.2                                                                     base    92a-8s                                                                             143                                   19                                      AcOEt                                 45287 20                                                                           H    4-OH   2                                                                                ##STR36##                                                                            base    75a-25s                                                                            181 i-PrOH                            45288 21                                                                           H    4-OH   2                                                                                ##STR37##                                                                            base    85a-15s                                                                            126 i-PrOH                            45289 A 22                                                                         H    4-OH   3                                                                                ##STR38##                                                                            fumarate                                                                              90a-10s                                                                            218 EtOH                              46349 A                                                                            2-F  4-OH   2 N(CH.sub.3).sub.2                                                                     oxalate 40a-60s                                                                            *                                     23                                                                            46349 C                                                                            2-F  4-OH   2 N(CH.sub.3).sub.2                                                                     methane s    142                                   24                         sulfonate    tert-BuOH                             46349 D                                                                            2-F  4-OH   2 N(CH.sub.3).sub. 2                                                                    hemi-   s    130-145                               25                         sulfate      H20                                   46349 E                                                                            2-F  4-OH   2 N(CH.sub.3).sub.2                                                                     phosphate                                                                             s    130-150                               26                                      H20                                   46349 F                                                                            2-F  4-OH   2 N(CH.sub.3).sub.2                                                                     maleate s    140                                   27                         acide        H20                                   46349 G                                                                            2-F  4-OH   2 N(CH.sub.3).sub.2                                                                     Hydro-  s    *                                     28                         chloride                                           46615 A                                                                            2-F  4-OH   2 N(CH.sub.3).sub.2                                                                     hemi-   a    *                                     29                         fumarate                                           46564 A                                                                            2-F  4-OCH.sub.3                                                                          2 N(CH.sub.3).sub.2                                                                     oxalate 20a-80s                                                                            *                                     30                                                                            46220 B                                                                            2-Cl 4-OH   2 N(CH.sub.3).sub.2                                                                     hemi-   s    198-200                               31                         fumarate     EtOH                                  46251 A                                                                            2-Cl 4-OCH.sub.3                                                                          2 N(CH.sub.3).sub.2                                                                     oxalate 30a-70s                                                                            118-123                               32                                      CH.sub.2 Cl.sub.2 /                                                           ether                                 46110 A                                                                            2-Cl 4-OCH.sub.3                                                                          3 N(CH.sub.3).sub.2                                                                     oxalate 40a-60s                                                                            127                                   33                                      acetone                               46190 A                                                                            2-Cl 4-OCH.sub.3                                                                          3 N(CH.sub.3 ).sub.2                                                                    oxalate s    147                                   34                                      BuOH/ether                            46278 A                                                                            2-Br 4-OCH.sub.3                                                                          2 N(CH.sub.3).sub.2                                                                     oxalate 30a-70s                                                                            *                                     35                                                                            46217 A                                                                            2-CH.sub.3                                                                         4-OCH.sub.3                                                                          2 N(CH.sub.3).sub.2                                                                     oxalate 15a-85s                                                                            96                                    36                                      i-PrOH                                45743 A                                                                            2-OCH.sub.3                                                                        4-OCH.sub.3                                                                          2 N(CH.sub.3).sub.2                                                                     base    54a-46s                                                                            158                                   37                                      EtOH                                  46057                                                                              2-OCH.sub.3                                                                        4-OH   3 N(CH.sub.3).sub.2                                                                     base    80a-20s                                                                            158                                   38                                      EtOH/H20                              46057 A                                                                            2-OCH.sub.3                                                                        4-OH   3 N(CH.sub.3).sub.2                                                                     oxalate a    151                                   39                                      EtOH/ether                            46109                                                                              2-OCH.sub.3                                                                        4-OH   3 N(CH.sub.3).sub.2                                                                     base    10a-90s                                                                            129                                   40                                      EtOH                                  46289 A                                                                            2-OCH.sub.3                                                                        4-OH   3 N(CH.sub.3).sub.2                                                                     base    52a-48s                                                                            *                                     41                                                                            46219 A                                                                            2-OCH.sub.3                                                                        4-OCH.sub.3                                                                          3 N(CH.sub.3).sub.2                                                                     oxalate a    147                                   42                                      CH.sub.2 Cl.sub.2                     46165 A                                                                            2-OCH.sub.3                                                                        4-OCH.sub.3                                                                          2 N(CH.sub.3).sub.2                                                                     oxalate 30a-70s                                                                            146                                   43                                      i-PrOH                                46175                                                                              2-NO.sub.2                                                                         4-OH   2 N(CH.sub.3).sub.2                                                                     base    s    127-135                               44                                      CH.sub.2 Cl.sub.2 /                                                           ether                                 46400                                                                              2-CF.sub.3                                                                         4-OH   2 N(CH.sub.3).sub.2                                                                     base    50a-50s                                                                            *                                     45                                                                            45678                                                                              2-NO.sub.2                                                                         4-OH   2 N(CH.sub.3).sub.2                                                                     base    93a-7s                                                                             180                                   46                                      CH.sub.3 CN                           45573                                                                              4-F  4-OH   2 N(CH.sub.3).sub.2                                                                     base    75a-25s                                                                            188                                   47                                      EtOH                                  45174 A                                                                            4-Cl 4-OH   2 N(CH.sub.3).sub.2                                                                     Hydrochloride                                                                         a    218                                   48                                      EtOH                                  45574 A                                                                            4-I  4-OH   2 N(CH.sub.3).sub.3                                                                     hemi    s    219                                   49                         oxalate      DMF                                   45290                                                                              4-I  4-OH   2 N(CH.sub.3).sub.2                                                                     base    a    183                                   50                                      AcOEt                                 45291                                                                              4-OH 4-OH     N(CH.sub.3).sub.2                                                                     base    75a-25s                                                                            265                                   51                                      DMF/EtOH                              45681 A                                                                            H    4-N(CH.sub.3).sub.2                                                                  2 N(CH.sub.3).sub.2                                                                     Hydrochloride                                                                         20a-80s                                                                            218                                   52                                      CH.sub.3 CN/                                                                  Ethyl                                                                         ether                                 45682 A                                                                            H    4-N(CH.sub.3).sub.2                                                                  2 N(CH.sub.3).sub.2                                                                     oxalate 70a-30s                                                                            162                                   53                                      CH.sub.3 CN                           46216 A 54                                                                         H                                                                                   ##STR39##                                                                           2 N(CH.sub.3).sub.2                                                                     oxalate s    150 acetone                           46025 A 55                                                                         H                                                                                   ##STR40##                                                                           2 N(CH.sub.3).sub.2                                                                     Hydrochloride                                                                         60a-40s                                                                            -- ether                              __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________    Examples 56 to 63                                                              ##STR41##                           (I)                                      Product                         F, °C.                                 n° SR          Salt or                                                                            Isomer                                                                             Solvent                                       Example No.                                                                          Ar     W1  W2  base % a-% s                                                                            recrystal.                                    __________________________________________________________________________    45099 A 56                                                                            ##STR42##                                                                           OH  H   hemi fumarate                                                                      anti 160 i-PrOH                                    45100 A 57                                                                            ##STR43##                                                                           OH  H   fumarate                                                                           syn  147 acetone                                   45097 58                                                                              ##STR44##                                                                           OH  H   base 80a-20s                                                                            130 CH.sub.3 CN                               45052 59                                                                              ##STR45##                                                                           OH  H   base 80a- 20s                                                                           139 AcOEt                                     46218 A 60                                                                            ##STR46##                                                                           OCH.sub.3                                                                         H   oxalate                                                                            43a-57s                                                                            *                                             46252 A 61                                                                            ##STR47##                                                                           OCH.sub.3                                                                         H   oxalate                                                                            s    156-164 EtOH/ether                            46039 62                                                                              ##STR48##                                                                           OH  OH  base 84a-16s                                                                            180 CH.sub.3 CN                               46134 63                                                                              ##STR49##                                                                           OCH.sub.3                                                                         OCH.sub.3                                                                         base 22a-78s                                                                            55-56 EtOH                                    __________________________________________________________________________

                                      TABLE 3                                     __________________________________________________________________________    Examples 64 to 66                                                              ##STR50##                              (I)                                   Product                                                                       n° SR        Salt                                                      Example             or      Isomer   Solvent                                  n°                                                                          Ar             base    % a-% s                                                                            F, °C.                                                                     recryst.                                 __________________________________________________________________________    45745 64                                                                            ##STR51##     Hydrochloride                                                                         48a-52s                                                                            178 i-PrOH                                   45746 65                                                                            ##STR52##     Hydrochloride                                                                         a    204 EtOH                                     45558 A 66                                                                          ##STR53##     maleate 90a-10s                                                                            144 i-PrOH                                   __________________________________________________________________________

EXAMPLE 67 Trans 1-(2-aminoethoxyimino) 1-phenyl 3-(4-hydroxyphenyl)2-propene acid oxalate: SR 45683 A ##STR54## a) Trans1-(2-bromoethoxyimino) 1-phenyl 3-(4-hydroxyphenyl) 2-propene

20 g of 4-hydroxy chalcone and 20 g of 1-oxyamino 2-bromoethanehydrobromide were mixed in solution in 200 ml absolute ethanol. Agitatethe reaction mixture at ambient temperature overnight, concentrate theethanol in vacuo, dissolve the residue in ethyl alcohol, filter theprecipitate and rinse it in ethyl ether.

1 M=33.7 g

b) SR 45683 A

1 g of the product obtained in a) hereinbefore was dissolved in 10 mlethanol saturated with ammonia.

The solution was left at ambient temperature for 10 days, and theethanol was concentrated in vacuo. Dissolve residue in water, makealkaline with sodium bicarbonate, extract with ethyl acetate, dry overmagnesium sulphate, filter and concentrate in vacuo. The residue wasdissolved when hot in 15 ml acetone, and 250 mg oxalic acid was added.The solution was allowed to return to ambient temperature and thecrystals were filtered, rinsed in acetone and recrystallized fromethanol, giving 180 mg of the anti isomer.

M.P.=210° C.

EXAMPLE 68 Trans 1-N,N-diisopropylaminoethoxyimino 1-phenyl3-(4-hydroxyphenyl) 2-propene hydrochloride: SR 45680 A ##STR55##

2 g of the product obtained as per Example 67a) hereinbefore wasdissolved in 10 ml dimethyl formamide. Add 10 ml diisopropylamine andheat the reaction mixture at 70° C. for 24 hours, concentrate in vacuo,dissolve residue in water, dry over magnesium sulphate and concentratein vacuo.

Chromatograph the residue on silca gel, using 90-10 (v.v) methylenechloride and methanol as eluent. The fractions of pure product wereconcentrated in vacuo. The residue was dissolved in ether, etherhydrochloride was added and the hydrochloride was precipitated andrecrystallized from acetonitrile, yielding 270 mg of the anti isomer.

M.P.=188° C.

EXAMPLE 69 Trans 1-N-methylaminoethoxyimino 1-(2-fluorophenyl)3-(4-hydroxyphenyl) 2-propene. SR 46616 A. ##STR56## a) 2-bromoN-ethoxycarbonyl N-methylethylamine dihydrobromide

197 ml of 30% soda was added to 540 ml water followed by 313 g of2-bromo N-methyl ethylamine hydrobromide. The mixture was cooled to 10°C. and 155 ml of ethyl chlorofomate was added, keeping the temperaturebelow 15° C. After agitation overnight at ambient temperature, theaqueous phase was decanted, extracted with ether, washed twice in waterand dried over magnesium sulphate, yielding 142 g of the expectedproduct.

b) N-(N-ethoxycarbonyl 2-N-methylaminoethoxy) phthalimide

The aforementioned derivative was added to a mixture of 108 g N-hydroxyphthalimide and 92.5 ml triethylamine in 100 ml DMF and heated at 87° C.for 3 days. The DMF was evaporated and the mixture was extracted withdichloromethane and washed with a solution of sodium carbonate and thenwith water. It was dried over magnesium sulphate and evaporated invacuo. The residue was redissolved in methanol and crystallized byadding water, obtaining 100 g of the expected product.

c) 2-N-methylaminoethoxyamine hydrobromide

A solution of 100 g of the aforementioned product was reflux-heated foran hour in a mixture of 366 mg HBr 46% and 246 ml acetic acid. Themixture was cooled to 5°, the insoluble substance was filtered, and thefiltrate was evaporated in vacuo. The residue was triturated hot intertiobutanol, yielding 22.1 g of the expected product.

d) SR 46616 A

A mixture of 4 g 2'-fluoro 4-hydroxy chalcone and 8.1 g hydroxylamine ashereinbefore was reflux-heated for 11/2 hours in 100 ml ethanol, thenevaporated to dryness in vacuo. The residue was treated with water,extracted twice with ether, made alkaline with sodium bicarbonate, andextracted with chloroform. The chloroform phase was washed with asolution of sodium bicarbonate, dried over MgSO₄ and evaporated,yielding 2.3 g of syn-anti mixture.

Hemifumarate

A mixture of 1.63 g of the aforementioned base and 300 mg of fumaricacid in ethanol was agitated for 30 minutes and left overnight at -15°C. 1.45 g of anti isomer was filtered. The filtrate was concentrated,yielding 140 mg of SR 46616A (a mixture of 70% syn and 30% anti).

The compounds listed in Table 4 were synthesized as per Examples 67, 68and 69.

                                      TABLE 4                                     __________________________________________________________________________    Examples 70 to 81                                                              ##STR57##                                                                     Examplen° SRProduct                                                         W.sub.1 '                                                                         W.sub.1                                                                           ##STR58##                                                                               baseSalt or                                                                         % a-% sIsomer                                                                      recrystal.SolventF, °C.             __________________________________________________________________________    45997 A                                                                            H   OH  NHCH.sub.3                                                                              base  43a-57s                                                                            160                                         70                                CH.sub.3 CN                                 45998 A                                                                            H   OH  NHCH.sub.3                                                                              base  a    122                                         71                                ether                                       46133                                                                              H   OH  NHCH.sub.3                                                                              oxalate                                                                             10s-90a                                                                            *                                           72                                                                            46386 A                                                                            Cl  OH  NH.sub.2  oxalate                                                                             a    *                                           73                                                                            46385 A                                                                            Cl  OH  NH.sub.2  oxalate                                                                             55a-45s                                                                            *                                           74                                                                            46384 A                                                                            Cl  OH  NHCH.sub.3                                                                              oxalate                                                                             50a-50s                                                                            *                                           75                                                                            46387 A                                                                            OCH.sub.3                                                                         OH  NH.sub.2  oxalate                                                                             90a-10s                                                                            *                                           76                                                                            46336 A                                                                            OCH.sub.3                                                                         OH  NHCH.sub.3                                                                              oxalate                                                                             77a-23s                                                                            *                                           77                                                                            46563 A                                                                            OCH.sub.3                                                                         OH  NHCH.sub.3                                                                              hemi- 50a-50s                                                                            *                                           78                     fumarate                                               46279                                                                              OCH.sub.3                                                                         OH  N(C.sub.2 H.sub.5).sub.2                                                                base  80a-20s                                                                            *                                           79                                                                            46132 80                                                                           OCH.sub.3                                                                         OH                                                                                 ##STR59##                                                                              base  46a-54s                                                                            *                                           46401 81                                                                           OCH.sub.3                                                                         OH                                                                                 ##STR60##                                                                              base  73a-27s                                                                            *                                           __________________________________________________________________________

EXAMPLE 82 Trans 1-N,N-dimethylaminoethoxyimino 1,3-diphenyl 2-propenehydrochloride: CM 40258 ##STR61##

A mixture of 5.1 g of the oxime of benzalacetophenone, 1.3 g of sodiumhydride in suspension in oil (55-60%) and 25 ml dimethylformamide wasagitated at 20° C. for an hour.

Then add 1.2 g sodium hydride in suspension in oil (55-60%) at 10°,followed by 4 g of 2-dimethylamino 1-chloroethane hydrochloride, andagitate the reaction mixture at 20° C. for 20 hours.

Pour the reaction mixture into 100 ml water, extract with ether, acidifywith a solution of hydrochloric acid, decant the aqueous phase, makealkaline with potassium carbonate, and decant 6.3 g of an oil which isreacted with a solution of hydrochloric acid in ethyl ether.Recrystallize the hydrochloride from acetone.

M=4.8 g

M.P.=209°-210° C.

EXAMPLE 83 Trans 2-chloro 1-N,N-dimethylaminoethoxyimino 1-phenyl3-(4-methoxyphenyl) 2-propene oxalate, syn. SR 46356 A ##STR62## a)2-chloro 3-(4-methoxyphenyl) 1-phenyl 2-propene 1-one

Prepared as per Z. Chem., Volume 19, 1979, 3.

b) SR 46356 A

1.4 g of the product obtained as in a) and 2 g of2-N,N-dimethylaminoethoxyamine dihydrochloride were dissolved in 40 mlabsolute ethanol and the reaction mixture was reflux-heated for 24hours. The ethanol was concentrated in vacuo, the residue was dissolvedin water and washed in ether, and the aqueous phase was made alkalinewith sodium bicarbonate, extracted with dichloromethane, dried andconcentrated in vacuo. The resulting oil was dissolved in 30 ml acetone,after which 1.5 g of oxalic acid was added. The oxalate was filtered andrecrystallized from ethanol, yielding 2.1 g of SR 46356 A.

The compounds listed in Table 5 were prepared as per Example 83.

                                      TABLE 5                                     __________________________________________________________________________    Examples 84 to 88                                                              ##STR63##                                                                    Product                                                                       n° SR         Salt         F, °C.                               Example              or      Isomer                                                                             Solvent                                     n°                                                                          W.sub.1 '                                                                        W.sub.1                                                                           M        base    %a-%s                                                                              recryst.                                    __________________________________________________________________________    46351 A                                                                            H  OCH.sub.3                                                                         Cl       oxalate 80a-20s                                                                            *                                           84                                                                            46348 A                                                                            H  OCH.sub.3                                                                         Br       oxalate s    172-180                                     85                                EtOH-                                                                         ether                                       46254 A                                                                            H  OH  (CH.sub.2).sub.2CH.sub.3                                                               oxalate 80a-20s                                                                            137-147                                     86                                CH.sub.2 Cl.sub.2 /                                                           ether                                       46253 A                                                                            H  OH  (CH.sub.2).sub.2CH.sub.3                                                               oxalate 30a-70s                                                                            189-193                                     87                                acetone                                     46163 A                                                                            Cl OH  CH.sub.2CH.sub.3                                                                       Hydrochloride                                                                         s    213                                         88                                EtOH                                        __________________________________________________________________________

                  TABLE 6                                                         ______________________________________                                        Main chemical displacements                                                   Example                                                                       No.    --N--(CH.sub.3)n                                                                         --N--CH.sub.2 --                                                                         --O--CH.sub.2 --                                                                       --OCH.sub.3                             ______________________________________                                        23     2,20       2,68       4.20     --                                      28     2.65       3,35       4,45     --                                      29     2,35       2,80       4,30     --                                      30     2,60 2,80  3,25 3,40  4,40 4,50                                                                              3,75                                    35     2,60 2,80  3,30 3,40  4,40 4,50                                                                              3,75                                    41     2,10 2,15  2,15 2,30  4,00 4,10                                                                              3,70                                    45     2,00 2,20  2,40 2,55  4,05 4,20                                                                              --                                      60     2,45 2,85  3,20 3,45  4,30 4,50                                                                              3,70                                    72     2,50 2,55  3,20       4,20     --                                      73     --         3,05       4,20     --                                      74     --         2,85 3,05  4,10 4,25                                                                              --                                      75     2,50 2,65  3,15 3,30  4,25 4,35                                                                              --                                      76     --         3,20       4,25     3,70                                    77     2,65       3,25       4,30     3,70                                    78     2,35 2,50  2,85 3,10  4,10 4,25                                                                              3,70                                    79     --         2,40 2,55  4,00 4,15                                                                              3,70                                    80     --         2,35 2,50  4,10 4,20                                                                              3,70                                                      2,60 2,70                                                   81     --         2,50 2,60  4,00 4,10                                                                              3,70                                                      2,70 2,80                                                   84     2,65 2,70  3,30 3,40  4,40 4,50                                                                              3,80                                    ______________________________________                                    

We claim:
 1. An intermediate compound useful in preparing propenoneoxime ethers, said intermediate compound having the formula: ##STR64##in which M is selected from the group consisting of H, Cl, Br and astraight or branched C₁ -C₆ alkyl; excluding the compounddi-1,3-(2-thienyl)2-propen-1-one.